Designed by architect Henry Beaumont Herts in 1912, it was named for Longacre Square, the original name for Times Square. The French neo-classical building was constructed by impresario Harry Frazee, better remembered as the owner of the Boston Red Sox who, needing money for his theatrical ventures, sold Babe Ruth's contract to the New York Yankees. A curse allegedly lingers on the theater as a result, and superstitious producers avoid it for fear they'll be backing a flop, as noted by William Goldman in his seminal book The Season: A Candid Look at Broadway. Despite the rumor, a large number of performers who have appeared on stage here have taken home a Tony Award for their efforts.

After Frazee fell into financial difficulties, the theatre changed hands many times before being sold to Astor Theatre Incorporated, a Shubert subsidiary, in 1919. WOR leased it from 1943-1953 as a radio and television playhouse.

After a decade in radio and television, the Longacre reopened as a theatrical venue in 1953 with Dorothy Parker's The Ladies of the Corridor. Star turns at the Longacre included Julie Harris in Mademoiselle Colombe (1954) (also featuring Robert Redford), The Lark (1955), and Little Moon of Alban (1960); Zero Mostel in Rhinoceros (1961); Ossie Davis in Purlie Victorious (1961); and Hal Holbrook in Mark Twain Tonight (1966).

Some other significant shows of the 1960s, 1970s and 1980s were A Case of Libel (1963), Lorraine Hansberry's The Sign in Sidney Brustein's Window (1964), Robert Anderson's I Never Sang for My Father (1968), Terrence McNally's The Ritz (1975), Harold Pinter's No Man's Land (1976) starring John Gielgud, a revival of The Basic Training of Pavlo Hummel (1977) featuring Al Pacino, and the Shubert-produced hits Ain't Misbehavin' (1978) and Children of a Lesser God (1980).